Antibiotics 2018

Patient-specific susceptibility results are rarely available, leaving
practitioners to choose therapies based upon general patterns of
susceptibility for that type of virus (HIV is a notable exception, where
susceptibility testing is a standard of care). While viruses can be cultured,
many viral illnesses are diagnosed through genetic testing for viral antigens
or nucleic acids. These tests can be followed quantitatively to see if an
infection improves, but symptoms are usually followed instead. Most commonwww.allmedicalbooks.com
viral infections have no effective pharmacotherapeutic remedy, which is a
fancy way of saying that there is still \u201cno cure for the common cold.\u201d
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34: Anti-Herpes Simplex Virus and
Varicella-Zoster Virus Agents
Agents: acyclovir, valacyclovir, famciclovir
These agents are primarily used in the treatment of infections caused by
herpes simplex virus (HSV) and varicella-zoster virus (VZV), though they are
active against some other viruses as well. Acyclovir is poorly absorbed and
must be given up to five times daily when administered orally; valacyclovir
and famciclovir are pro-drugs that are absorbed better and can be
administered less frequently. Only acyclovir can be administered
intravenously, and it is the agent of choice for serious HSV infections such as
encephalitis.
Mechanism of Action
These drugs are nucleoside analogs that, after phosphorylation, are
incorporated into the elongating viral DNA strand just like cellular nucleotides;
but they lack the functional group that allows the next nucleotide to be added,
halting replication.
Spectrum
Good: HSV-1 and HSV-2
Moderate: VZV
Poor: Epstein-Barr virus (EBV), cytomegalovirus (CMV), HIV
Adverse Effects
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Adverse Effects
These drugs are generally well tolerated with few adverse effects. The most
concerning adverse effect is nephrotoxicity through either crystallization or
acute interstitial nephritis (AIN), most commonly associated with IV acyclovir
in higher doses. Crystallization is preventable through hydration and correct
dosing in renally impaired patients. Seizures, tremors, or other CNS effects
can also occur. Nausea, diarrhea, and rash are more common. Thrombotic
thrombocytopenic purpura has been reported with valacyclovir in HIV
patients.
Important Facts
Valacyclovir is a pro-drug of acyclovir with substantially improved
bioavailability and less-frequent dosing. Its disadvantage is higher cost.
Famciclovir is a pro-drug of penciclovir, an agent that is available only as
a topical preparation.
Acyclovir dosing varies widely by indication and host status. Be sure to
double-check that it is appropriate for your patients.
Acyclovir is most nephrotoxic in combination with diuretics or other
nephrotoxins. Keep your patients hydrated during acyclovir therapy,
particularly if it is given in higher IV doses.
What They\u2019re Good For
Acyclovir is the drug of choice for severe or difficult-to-treat HSV infections,
such as encephalitis or severe HSV outbreaks among HIV patients. Any of
these agents can be used to treat HSV-2 infections (genital herpes) to
prevent outbreaks or decrease symptom duration. They are all also effective
in treating VZV infection.
Don\u2019t Forget!
Make sure your patient can afford valacyclovir or famciclovir before
prescribing either one. Oral acyclovir is less convenient, but much less
expensive.
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35: Anti-cytomegalovirus Agents
Agents: ganciclovir, valganciclovir, foscarnet,
cidofovir
Cytomegalovirus (CMV) causes infections that are usually asymptomatic in
immunocompetent patients but can be devastating in immunocompromised
patients. Approximately 60% of Americans become seropositive for CMV by
adulthood, and infection is lifelong. If a patient becomes
immunocompromised, the infection can reactivate and the patient will need
pharmacotherapy. Anti-cytomegalovirus agents work by preventing viral
replication. They also all have appreciable toxicity that must be respected
and monitored.
Mechanisms of Action
Ganciclovir is a nucleoside analogue that, after phosphorylation, is integrated
into viral DNA by DNA polymerase, halting viral replication. Valganciclovir is a
pro-drug of ganciclovir. Cidofovir is a nucleotide analogue that has a similar
mechanism to ganciclovir.
Foscarnet is a pyrophosphate analogue that acts as a noncompetitive
inhibitor of the DNA and RNA polymerases of multiple viruses.
Spectrum
Good: CMV, HSV-1, HSV-2, VZV, EBV
Poor: HIV
Adverse Effects
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Adverse Effects
Ganciclovir and valganciclovir are the same active drug and have the same
adverse reactions. They both have dose-dependent myelosuppression that is
relatively common, particularly when used in higher doses or in renally
impaired patients without dose adjustment. Foscarnet is nephrotoxic and
neurotoxic, and it is reserved for patients who have failed other therapy.
Nausea, vomiting, and diarrhea can occur from any of these agents.
Foscarnet can also cause penile ulcers. Cidofovir is an uncommonly used
agent that also exhibits nephrotoxicity.
Important Facts
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Important Facts
Oral ganciclovir has been replaced by valganciclovir, which has much
better bioavailability.
Ganciclovir must be carefully dosed by patient weight and renal function.
Monitor patients closely for changes in renal function when they are on
therapy.
The package insert for valganciclovir specifies dose adjustment for renal
dysfunction but not weight. It comes in two strengths: 900 mg and 450
mg. The dose of 900 mg BID is considered to be equivalent to 5 mg/kg
q12h of IV ganciclovir, but it may be much more than that for an
underweight patient because it is approximately 60% bioavailable.
Consider this example for a 50-kg patient:
Ganciclovir dose = 50 kg × 5 mg/kg = 250 mg ganciclovir
Valganciclovir dose = 900 mg × 0.60 bioavailability = 540 mg of active
ganciclovir
This patient would receive more than double the amount of active
ganciclovir if 900 mg BID of valganciclovir were used. It thus may be
worth considering dose reduction in underweight patients, particularly if
they are at high risk of toxicity.
The nephrotoxicity of foscarnet and cidofovir is such that both require
extensive prehydration regimens with normal saline to reduce the toxicity
risk. Cidofovir actually requires coadministration with probenecid, which
reduces the excretion of cidofovir into the renal tubules and attenuates its
toxicity.
It takes awhile, but genotype-based susceptibility testing is available for
CMV and is usually performed if resistance is suspected in patients not
responding to ganciclovir. The genotype will reveal whether ganciclovir
resistance is present and whether cidofovir or foscarnet are therapeutic
options.
What They\u2019re Good For
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What They\u2019re Good For
Ganciclovir and valganciclovir are first-line drugs for the treatment and
prevention of CMV infections. Valganciclovir is often given to prevent CMV
infection after transplant. Foscarnet is a second-line agent for CMV that can
also be used for severe or resistant HSV infections. Cidofovir is a second-line
agent for CMV.
Don\u2019t Forget!
Although valganciclovir is oral, it is has good bioavailabity and has adverse
effects identical to those of ganciclovir. Valganciclovir use requires monitoring
for toxicity that is just as rigorous as that for intravenous ganciclovir.
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36: Neuraminidase Inhibitors
Agents: oseltamivir, peramivir, zanamivir
The neuraminidase inhibitors are anti-influenza virus drugs that have activity
against influenza A and B strains, unlike amandatine and rimantidine, older
drugs that are active only against influenza A strains. They work by
preventing the viral neuraminidase enzyme from releasing new virions